ASF1B promotes erythropoiesis by regulating the establishment and enrichment of H3.3 nucleosomes

Histone chaperone ASF1B is largely known to be functionally correlated with cell proliferation and cell cycle. We found that the expression of ASF1B was abundant together with histone variant H3.3 during in mouse fetal liver cells. However, the mechanism underlying this coordination is still unclear. HIRA, a H3.3 specific chaperone, was dispensable in fetal hematopoiesis. In contrast, we found that ASF1B predominantly regulated H3.3 encoding genes and erythroid genes, whereas ASF1A served a compensatory function. Notably, ASF1B occupied >70% of H3.3 nucleosomes and determined H3.3 enrichment at erythroid gene promoters and enhancers. However, loss of ASF1B de-repressed the expression of embryonic/fetal globin genes by altering enrichment of H3.3 and erythroid transcription factors as well as chromatin accessibility. The regulatory pathway of ASF1B in H3.3 enrichment involved the recruitment of chromatin remodeler BRG1 and accumulation of H3K27ac in active chromatin. In summary, ASF1B plays a crucial role in enrichment of H3.3 nucleosomes and establishment of the chromatin environment to affect erythroid gene expression, highlighting the therapeutic potential of ASF1B in targeting erythrocyte disorders, such as β-globin hemoglobinopathies.